Role for Poly(ADP-ribose) Polymerase Activation in Diabetic Nephropathy, Neuropathy and Retinopathy

Abstract

Chronic complications of diabetes mellitus e.a. diabetic nephropathy, neuropathy and retinopathy develop in at least 30-50% of patients with both Type 1 (insulin-dependent) and Type 2 (non-insulin-dependent) diabetes, and are the major cause of increased morbidity and mortality. The ultimate consequences of diabetes complications include renal failure, foot ulceration and amputation, and blindness. The magnitude of the problem and its economic impact make extremely important to understand the natural history of chronic diabetes complications and to identify more successful preventive and therapeutic options. The pathogenesis of diabetes complications involves multiple mechanisms. The importance of vascular component is well recognized in diabetic retinopathy, which is primarily a vascular disease, as well as diabetic nephropathy developing as a result of complex interplay between hemodynamic and metabolic factors. The importance of vascular versus non-vascular mechanisms in the pathogenesis of diabetic neuropathy remains a subject of debate. Studies in animal and cell culture models revealed that such mechanisms as increased aldose reductase activity, non-enzymatic glycation/glycoxidation, activation of protein kinase C, impaired growth factor support, enhanced oxidative/nitrosative stress, and its downstream effectors such as mitogen-activated protein kinase activation, inflammatory response, endothelin-1 overexpression and impaired Ca(++) signaling, play an important role in all three tissue-targets for diabetes complications i.e. kidney, retina and peripheral nerve. Evidence for important role of the downstream effector of free radical and oxidant-induced DNA injury, poly(ADP-ribose) polymerase activation, is emerging. This review describes recent studies addressing the role for poly(ADP-ribose) polymerase activation in diabetic nephropathy, neuropathy and retinopathy.

Aldose reductase inhibitor fidarestat counteracts diabetes-associated cataract formation, retinal oxidative-nitrosative stress, glial activation, and apoptosis

“…PARP activation. PARP activation results in NAD + depletion and energy failure, changes in transcriptional regulation and gene expression, the accumulation of glutamate and cytosolic Ca ++ , and mitogen-activated protein kinase activation (9,10,52). Evidence for the important role of PARP activation in diabetic endothelial dysfunction, peripheral and autonomic neuropathy, cardiomyopathy, retinopathy and nephropathy is emerging (9,10,52-58).…”

“…Multiple mechanisms including increased sorbitol pathway activity (1,2), non-enzymatic glycation and glycoxidation (3,4), enhanced oxidative-nitrosative stress (5,6), protein kinase C (7,8), poly(ADP-ribose) polymerase (9,10) and lipoxygenase (11,12) activation, and others have been implicated in the pathogenesis of chronic diabetic complications. The relations between individual mechanisms are not completely understood and require specific studies.…”

Peripheral neuropathy in mice with neuronal nitric oxide synthase gene deficiency

“…Evidence for the important role for PARP activation in diabetic complications including endothelial dysfunction (49), cardiomyopathy (50), peripheral (14)(15)(16)(17) and autonomic (51) neuropathy, nephropathy (52), and retinopathy (53,54) is emerging. Accumulation of poly(ADP-ribosyl)ated proteins, a sign of PARP activation, has been documented in peripheral nerve and DRG neurons of animal models of Type 1 and Type 2 diabetes and high glucose-exposed cultured human Schwann cells (6)(7)(8)(9)(10)(11)(14)(15)(16)(17)22,35,55) PARP activation has been implicated in neurovascular dysfunction, motor and sensory nerve conduction velocity deficits, peripheral nerve energy failure, thermal hyper-and hypoalgesia, mechanical hypoalgesia, tactile allodynia, and intraepidermal nerve fiber loss characteristic for PDN (14)(15)(16)(17)56). In the present study, PARP activation was clearly manifest in both sciatic nerve and DRG of diabetic wild-type mice consistent with our previous studies (6,8,9,11).…”

Intertwined Role of Reactive Oxygen, Nitrogen and Carbon in Diabetic State

“…NADPH is an important cofactor necessary to regenerate reduced glutathione. Depletion of GSH could exacerbate intracellular oxidative stress and thereby contribute to diabetic complications [26]. Inhibition of polyol pathway is a potential treatment of diabetic neuropathy.…”

“…NADPH is an important cofactor to produce reduced glutathione, (GSH) and GSH is a scavenger of reactive oxygen species (ROS). Depletion of GSH could exacerbate intracellular oxidative stress and thereby contribute to diabetic complications [26]. …”